The invention disclosed herein concerns a beta-methyl-hydroxymethyl ketone, and process for synthesis thereof, which is a key intermediate used in making beta-methyl carbapenems. 1-beta methyl carbapenem antibiotics, are particularly well known for treating a broad spectrum of gram-negative and gram-positive bacterial infections. See for example U.S. Pat. No. 4,962,103 issued Oct. 9, 1990; U.S. Pat. No. 4,933,333; U.S. Pat. No. 4,943,569; U.S. Pat. No. 5,122,604; U.S. Pat. No. 5,034,384 and U.S. Pat. No. 5,011,832.
Numerous routes to beta-methyl carbapenem intermediates of formula 6 have been cited in the literature: ##STR2## Tetrahedron Letters, Vol. 26, No. 39, pp 4739-4742, 1985; J. Am. Chem. Soc. 1986, 108, 4673-3675; Tetrahedron Letters, Vol. 27, No. 19, pp 2149-2152, 1986; Can. J. Chem. 65, 2140 (1987); Can. J. Chem. 66, 1400 (1988); Chemistry Letters, pp 445-448, 1989; Tetrahedron Letters, Vol. 31, No. 2, pp 271-274, 1990; Tetrahedron Letters, Vol 31, No. 4, pp 549-552, 1990; J. Org. Chem. 1992, 57, 2411-2418; and the like.
Previous methods of stereoselective preparation of beta-methyl carbapenems include:
(1) hydrogenation of a 4-(2-propenyl) substituted azetidinone. PA1 (2) stereoselective protonation of an enolate ion PA1 (3) reaction of 4-acetoxyazetidinone with a chiral enolate. PA1 R.sup.b and R.sup.c are independently: PA1 R.sup.1 is an alkylsilyl protecting group corresponding to the silylating agent employed; PA1 R.sup.b and R.sup.c are independently: PA1 (a) reacting a ketoester of formula 1: ##STR10## wherein R.sup.b and R.sup.c are independently: PA1 (c) combining the isolated ketoester of formula 4 with an acid and a first catalyst at a temperature of about 0.degree. C. to about 50.degree. C. with about 0-500 psig H.sub.2, to give a compound of formula 5: ##STR14## (d) selectively desilylating with a desilylating agent at a temperature of about -10.degree. C. to about 50.degree. C. to yield the compound of formula 6: ##STR15## (e) dissolving the compound of formula 6 in an alcohol and hydrogenating at about 30 to about 55 psig H.sub.2 in the presence of a second catalyst at a temperature of about 0.degree. C. to about 100.degree. C., to yield compound I and PA1 (f) purifying and isolating compound I.
These methods require difficult multi-step preparation, tedious manipulation of highly reactive intermediates at low temperature, or use of expensive reagents.
The instant invention discloses an efficient process for the synthesis of beta-methyl intermediates with high stereoselectivity from readily available starting materials.